Multidrug Resistance of a Continuously Differentiating Monoclonal B Lineage in the Blood and Bone Marrow of Patients with Multiple Myeloma

Abstract

Although multiple myeloma has long been regarded as a malignancy localized to the bone marrow, recent evidence clearly shows a monoclonal population of B cells in the blood of patients with myeloma both at diagnosis and during therapy. It is difficult however to determine whether or not these circulating tumor-related B cells are in fact malignant or if they are non-malignant relatives of the plasma cells in the bone marrow. Our working hypothesis predicts that circulating monoclonal B lineage cells are the precursors of the bone marrow plasma cells and that, contrary to well established dogma, traffic of myeloma cells travels from the blood to the bone marrow. We predict, and our data support the view, that B lineage cells localized in the bone marrow are predominantly end stage non-proliferating cells which have little or no propensity or capability to migrate, whose future options consist mainly of entry into apoptotic pathways and eventual death. If this view is correct, it predicts that the malignant stem cell in myeloma may be located outside the bone marrow. If the circulating monoclonal B lineage cells in blood are in fact malignant cells, then they either represent the stem cells themselves or are early descendents in the process of trafficking to the marrow where they will terminally differentiate. Spleen might be considered the most likely place of origin for myeloma as plasma cells of normal bone marrow originate in the spleen, migrate as antigen-activated B cells to the bone marrow via the blood and undergo terminal differentiation to antigen-specific plasma cells (1, 2), a pattern remarkably similar to that of the monoclonal B lineage in myeloma (3). Also consistent with this view is work indicating that the accumulation of plasma cells in normal bone marrow is the major site of antibody synthesis in the body, and increases with age (1). In myeloma, analysis of autopsy material indicated the least mature cells of the malignant lineage were in the spleen whereas considerably more terminally differentiated B lineage cells were found in blood (Jensen et al, submitted). This highly speculative hypothesis is a difficult one to test as events in the spleen would be predicted to occur in the earliest stages of the disease and cells might become extra-splenic even before diagnosis. Thus the properties and potential of the circulating blood B lineage cells have become an important target of investigation, and an even more crucial consideration in the design of new modes of therapy for myeloma patients.